5599228 PITFALLS IN DIAGNOSING THROMBOTIC THROMBOCYTOPENIC PURPURA IN SICKLE CELL DISEASE
Authors: D.A. TSITSIKAS, J. HALL, J. MAY, R. GANGARAJU, M.B. MARQUES, M. SCULLY
Journal: HemaSphere (2023)

Background: Thrombotic microangiopathies are diagnosed by thrombocytopenia, microangiopathic haemolytic anaemia and evidence of end organ damage. In TTP this includes neurological symptoms, renal impairment and cardiac microthrombi. Confirmation of the diagnosis is severe deficiency (<10%) of the metalloproteinase ADAMTS13 and/or the presence of an inhibitor. The diagnosis of TTP in sickle cell disease (SCD) can be challenging as SCD is characterised by a chronic state of haemolysis often with very abnormal peripheral blood morphology so clinical features suggestive of TTP can be due to complications of SCD. More specifically, the coexistence of neurological impairment and thrombocytopenia seen in fat embolism syndrome (FES) complicating SCD can lead to an erroneous diagnosis of TTP. FES typically affects non-homozygous patients and those with a previously mild course of their illness manifesting with respiratory failure, neurological signs, thrombocytopenia and potential involvement of any system leading to high morbidity and mortality. Peripheral blood morphology typically shows very high number of nucleated red blood cells (nRBC). Aims: To identify published cases of TTP in patients with SCD and review the diagnostic approach. Methods: A PubMed literature search was performed using the terms “sickle cell” and “thrombotic thrombocytopenic purpura”/”TTP”. Results: Of 19 cases identified, 9 were individual case reports and a case series of 10. All patients had very mild course of their SCD. The median nadir platelet count was 38 x 109/L (7-70). 84% had neurological involvement either at presentation or shortly afterwards; primarily altered sensorium/drop in GCS. 79% patients also had severe type I respiratory failure either preceding or occurring simultaneously with the development of neurological signs and associated with extensive changes on chest imaging. Schistocytes were identified in all cases but in the vast majority at relatively low levels; at the same time, all showed large numbers of nRBCs. 18 of the 19 cases were published after 1998; in 15 there was no mention of ADAMTS13 testing at all. In the 3 cases with ADAMTS13 levels, all were normal; 2 samples were obtained before therapeutic plasma exchange (TPE) and 1 after. 18 patients received TPE and 1 an infusion of donor plasma. However, prior to TPE, all patients had already received red cell transfusion achieving Hb S levels of 30% or less. There were 2 (11%) deaths while the remainder of patients achieved complete recovery. One due to intracranial haemorrhage and the other, sepsis in the context of immunosuppression for prevention of TTP recurrence. The presence of early respiratory failure, the inconclusive morphological findings, the degree of thrombocytopenia, and the complete absence of confirmatory ADAMTS13 results bring the diagnosis of TTP to question in all cases. Given the clinical presentations, we suspect that some of these patients had FES. The positive outcomes may be explained by the fact that all patients received adequate red cell transfusion, but also the possible beneficial effect of TPE in acute complications of SCD with a hyper inflammatory component such as FES. Conclusion: The diagnosis of TTP in patients with SCD is challenging due to many overlapping features. It should not be made without confirmatory ADAMTS13 results and the possibility of alternative diagnoses should be explored. References 1. Lee HE, Marder VJ, Logan LJ, Friedman S, Miller BJ. Life-threatening thrombotic thrombocytopenic purpura (TTP) in a patient with sickle cell-hemoglobin C disease. Ann Hematol. 2003 Nov;82(11):702-4. 2. Bolanos-Meade, J., Keung, Y.K., Lopez-Arvizu, C., Florendo, R. and Cobos, E., 1999. Thrombotic thrombocytopenic purpura in a patient with sickle cell crisis. Annals of hematology, 78(12), pp.558-559. 3. Shome, D.K., Ramadorai, P., Al-Ajmi, A., Ali, F. and Malik, N., 2013. Thrombotic microangiopathy in sickle cell disease crisis. Annals of hematology, 92(4), pp.509-515. 4. Vlachaki E, Agapidou A, Neokleous N, Adamidou D, Vetsiou E, Boura P. Thrombotic thrombocytopenic purpura or immune thrombocytopenia in a sickle cell/β+-thalassemia patient: a rare and challenging condition. Transfus Apher Sci. 2014 Oct;51(2):175-7. 5. Chehal A, Taher A, Shamseddine A. Sicklemia with multi-organ failure syndrome and thrombotic thrombocytopenic purpura. Hemoglobin. 2002 Nov;26(4):345-51. 6. Geigel EJ, Francis CW. Reversal of multiorgan system dysfunction in sickle cell disease with plasma exchange. Acta Anaesthesiol Scand. 1997 May;41(5):647-50. 7. Chinowsky MS. Thrombotic thrombocytopenic purpura associated with sickle cell-hemoglobin C disease. South Med J. 1994 Nov;87(11):1168-71. 8. Adamski J, Hanna CA, Reddy VB, Litovsky SH, Evans CA, Marques MB. Multiorgan failure and bone marrow necrosis in three adults with sickle cell-β+ -thalassemia. Am J Hematol. 2012 Jun;87(6):621-4. 9. Kammeyer R, Devnani R, Mehta R. Cerebral fat embolism syndrome mimicking thrombotic thrombocytopenic purpura in a patient with hemoglobin SC disease. Am J Hematol. 2016 May;91(5):539-42